Identification of immune responses that can help control equine infectious anemia virus (EIAV) seems important because similar mechanisms may be applicable to other lentivirus infections. Reasons for assuming that immunological responses involved in protection against EIAV can be identified are based on eventual control of the disease in horses and on the demonstration that lymphocyte responses are responsible for the control. The decrease of initial plasma viremia to undetectable levels in infected horses is associated with the appearance of CD8+ cytotoxic T lymphocytes (CTL), while neutralizing antibody often is undetectable until after clearance of the plasma viremia. The requirement for pathogen-specific CD4+ helper T lymphocyte (HTL) activity of the Th1 subset, as determined by cytokine production, for effective CTL responses is well documented. In addition, there are studies in different viral systems that demonstrate the efficacy of using only HTL epitopes that elicit a strong CD4+ Th1 response to enhance both proliferative and CTL activity upon subsequent virus challenge. Such an approach for lentivirus vaccines might overcome the difficulty of identifying both universal CTL and HTL epitopes which are presented by a broad range of major histocompatibility complex class I or class II molecules, respectively. This is because there is evidence indicating that such universal HTL epitopes may be more common than universal CTL epitopes. Further, HTL epitopes have been located in conserved regions of lentiviruses possibly circumventing another key problem of antigenic variation. Our long-term research goal is to determine the roles of HTL and CTL in the control of lentiviral infections and to achieve this goal we particularly need more knowledge of the contribution of CD4+ T lymphocytes to this immunity. To that end, the experiments outlined in this proposal will directly test the hypothesis that induction of CD4+ Th1 lymphocyte responses to universal and conserved EIAV epitopes will promote enhanced CTL responses to, and afford protection against, subsequent EIAV challenge.